Glycogen storage disease type II (GSD-II) (also known as Pompe disease or acid maltase deficiency) is a fatal genetic muscle disorder caused by a deficiency of acid α-glucosidase (GAA), a glycogen degrading lysosomal enzyme (Hirschhorn, R., “Glycogen storage disease type II: acid α-glucosidase (acid maltase) deficiency”, in Scriver, C. R. et al., (eds) The Metabolic and Molecular Basis of Inherited disease, 7th Ed., McGraw-Hill, New York, 1995, pp. 2443–2464). The deficiency results in lysosomal glycogen accumulation in almost all tissues of the body, with cardiac and skeletal muscle being the most seriously affected. The combined incidence of all forms of GSD-II is estimated to be 1:40,000, and the disease affects all groups without an ethnic predilection (Martiniuk, F. et al., Amer. J. Med. Genet. 79:69–72 (1998); Ausems, M. G. E. M. et al., Eur. J. Hum. Genet. 7:713–716 (1999)).
Clinically, GSD-II encompasses a range of phenotypes differing as to age of onset, organs involved and clinical severity, generally correlating with the residual amount of GAA activity. In its most severe presentation (infantile GSD-II, or Pompe disease, in which less than 1% of normal GAA activity is present), infants are affected by a hypertrophic cardiomyopathy, generalized muscle weakness and hypotonia secondary to massive glycogen accumulation in cardiac and skeletal muscles (for review, see Hirschhorn, supra). The disease progresses rapidly, with death from cardiac failure usually occurring by 1 year of age. Juvenile (1–10% of normal GAA activity) and adult-onset (10–40% of normal GAA activity) forms of the disease are characterized by lack of severe cardiac involvement, later age of onset, and slower progression, but eventual respiratory or limb muscle involvement results in significant morbidity and mortality for the affected individuals.
Drug treatment strategies, dietary manipulations, and bone marrow transplantation have been employed as means for treatment for GSD-II, without significant success (Hug, G. et al., Birth Defects Org. Ser. 9:160–183 (1967); Slonim, A. E. et al., Neurology 33:34 (1983); Watson, J. G. et al., N. Engl. J. Med. 314:385 (1986)). Early attempts at enzyme replacement were also unsuccessful (Hug, G. and Schubert, W. K., J. Clin. Invest. 46:1073 (1967); de Barsy, T. et al., Birth Defects Orig. Art. Ser. 9:84–190 (1973); Williams, J. C. and Murray, A. K., “Enzyme replacement in Pompe disease with an alpha glucosidase low-density lipoprotein complex”, in Desnick, R. J. (ed), Enzyme Therapy in Genetic Diseases: 2, New York, Alan R. Liss 1980; pp. 415–423)). A need remains for effective treatment of GSD-II.